scholarly journals Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3

2008 ◽  
Vol 205 (7) ◽  
pp. 1551-1557 ◽  
Author(s):  
Cindy S. Ma ◽  
Gary Y.J. Chew ◽  
Nicholas Simpson ◽  
Archana Priyadarshi ◽  
Melanie Wong ◽  
...  
Keyword(s):  
Th17 Cells ◽  
Immunoglobulin E ◽  
Orphan Receptor ◽  
Primary Immune Deficiency ◽  
Interleukin 17 ◽  
Th 17 ◽  
Infection Susceptibility ◽  
Fungal Antigens

Hyper–immunoglobulin E syndrome (HIES) is a primary immune deficiency characterized by abnormal and devastating susceptibility to a narrow spectrum of infections, most commonly Staphylococcus aureus and Candida albicans. Recent investigations have identified mutations in STAT3 in the majority of HIES patients studied. Despite the identification of the genetic cause of HIES, the mechanisms underlying the pathological features of this disease remain to be elucidated. Here, we demonstrate a failure of CD4+ T cells harboring heterozygous STAT3 mutations to generate interleukin 17–secreting (i.e., T helper [Th]17) cells in vivo and in vitro due to a failure to express sufficient levels of the Th17-specific transcriptional regulator retinoid-related orphan receptor γt. Because Th17 cells are enriched for cells with specificities against fungal antigens, our results may explain the pattern of infection susceptibility characteristic of patients with HIES. Furthermore, they underscore the importance of Th17 responses in normal host defense against the common pathogens S. aureus and C. albicans.

scholarly journals CD69 Association with Jak3/Stat5 Proteins Regulates Th17 Cell Differentiation

2010 ◽  
Vol 30 (20) ◽  
pp. 4877-4889 ◽  
Author(s):  
Pilar Martín ◽  
Manuel Gómez ◽  
Amalia Lamana ◽  
Arantxa Cruz-Adalia ◽  
Marta Ramírez-Huesca ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Th17 Cells ◽  
T Cell Differentiation ◽  
Orphan Receptor ◽  
Interleukin 17 ◽  
Deficient Mice

ABSTRACT T-cell differentiation involves the early decision to commit to a particular pattern of response to an antigen. Here, we show that the leukocyte activation antigen CD69 limits differentiation into proinflammatory helper T cells (Th17 cells). Upon antigen stimulation in vitro, CD4+ T cells from CD69-deficient mice generate an expansion of Th17 cells and the induction of greater mRNA expression of interleukin 17 (IL-17), IL 23 receptor (IL-23R), and the nuclear receptor retinoic acid-related orphan receptor γt (RORγt). In vivo studies with CD69-deficient mice bearing OTII T-cell receptors (TCRs) specific for OVA peptide showed a high proportion of antigen-specific Th17 subpopulation in the draining lymph nodes, as well as in CD69-deficient mice immunized with type II collagen. Biochemical analysis demonstrated that the CD69 cytoplasmic tail associates with the Jak3/Stat5 signaling pathway, which regulates the transcription of RORγt and, consequently, differentiation toward the Th17 lineage. Functional experiments in Th17 cultures demonstrated that the selective inhibition of Jak3 activation enhanced the transcription of RORγt. Moreover, the addition of exogenous IL-2 restored Stat5 phosphorylation and inhibited the enhanced Th17 differentiation in CD69-deficient cells. These results support the early activation receptor CD69 as an intrinsic modulator of the T-cell differentiation program that conditions immune inflammatory processes.

scholarly journals Plasma Levels of Eicosapentaenoic Acid Are Associated with Anti-TNF Responsiveness in Rheumatoid Arthritis and Inhibit the Etanercept-driven Rise in Th17 Cell Differentiationin Vitro

2017 ◽  
Vol 44 (6) ◽  
pp. 748-756 ◽  
Author(s):  
Louisa Jeffery ◽  
Helena L. Fisk ◽  
Philip C. Calder ◽  
Andrew Filer ◽  
Karim Raza ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Fatty Acid ◽  
Eicosapentaenoic Acid ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Interferon Γ ◽  
Interleukin 17 ◽  
Differentiationin Vitro

Objective.To determine whether levels of plasma n-3 polyunsaturated fatty acids are associated with response to antitumor necrosis factor (anti-TNF) agents in rheumatoid arthritis (RA), and whether this putative effect may have its basis in altering anti-TNF–driven Th17 cell differentiation.Methods.Plasma was collected at baseline and after 3 months of anti-TNF treatment in 22 patients with established RA, and fatty acid composition of the phosphatidylcholine (PC) component was measured. CD4+CD25− T cells and monocytes were purified from the blood of healthy donors and cocultured in the presence of anti-CD3, with or without etanercept (ETN), eicosapentaenoic acid (EPA), or the control fatty acid, linoleic acid (LA). Expression of interleukin 17 and interferon-γ was measured by intracellular staining and flow cytometry.Results.Plasma PC EPA levels and the EPA/arachidonic acid ratio correlated inversely with change in the Disease Activity Score at 28 joints (DAS28) at 3 months (−0.51, p = 0.007 and −0.48, p = 0.01, respectively), indicating that higher plasma EPA was associated with a greater reduction in DAS28. Plasma PC EPA was positively associated with European League Against Rheumatism response (p = 0.02). An increase in Th17 cells post-therapy has been associated with nonresponse to anti-TNF. ETN increased Th17 frequenciesin vitro. Physiological concentrations of EPA, but not LA, prevented this.Conclusion.EPA status was associated with clinical improvements to anti-TNF therapyin vivoand prevented the effect of ETN on Th17 cellsin vitro. EPA supplementation might be a simple way to improve anti-TNF outcomes in patients with RA by suppressing Th17 frequencies.

scholarly journals Monocytic MDSCs skew Th17 cells toward a pro-osteoclastogenic phenotype and potentiate bone erosion in rheumatoid arthritis

Rheumatology ◽  
2020 ◽  
Author(s):  
Shixian Chen ◽  
Chunqing Guo ◽  
Ran Wang ◽  
Zhitao Feng ◽  
Zheng Liu ◽  
...  
Keyword(s):  
Mouse Models ◽  
Th17 Cells ◽  
Bone Erosion ◽  
Joint Destruction ◽  
Bone Destruction ◽  
Suppressor Cells ◽  
Th 17 ◽  
Autoimmune Conditions

Abstract Objectives While myeloid-derived suppressor cells (MDSCs) were previously shown to promote a proinflammatory T helper (Th) 17 response in autoimmune conditions, a potential impact of the MDSC-Th17 immune axis on abnormal bone destruction in RA remains largely unknown. Methods We investigated the correlation between the frequency of MDSCs or its subsets and joint destruction in RA patients. The reciprocal actions of patient-derived MDSCs and Th17 cells were studied using osteoclast (OC) differentiation and bone resorption assays in vitro, which were further validated using mouse models of RA. Contribution of MDSCs to osteoclastogenesis and bone erosion in vivo was determined by depletion or transfer of MDSCs. Results Human MDSCs, particularly monocytic MDSCs (M-MDSCs), exhibit inherent OC-differentiating capacity and positively correlate with clinical bone erosion in RA patients. Strikingly, patient-derived M-MDSCs can program Th17 cells towards a pro-osteoclastogenic phenotype, which in return potentiates OC differentiation via the receptor activator of nuclear factor κΒ ligand (RANK-L)-RANK signalling. This enhanced osteolysis driven by the reciprocal actions of M-MDSCs and Th17 cells is further confirmed using mouse models of RA. Selective depletion of M-MDSCs significantly ameliorates osteoclastogenesis and disease severity in arthritic mice, whereas transfer of M-MDSCs aggravates bone erosion associated with increased OCs in recipient mice. Conclusion Our findings highlight the functional plasticity of MDSCs and identify a novel pro-osteoclastogenic pathway governed by interplay between myeloid cells and T lymphocytes in autoimmune RA.

scholarly journals Dihydroartemisinin Alleviates Imiquimod-Induced Psoriasis-like Skin Lesion in Mice Involving Modulation of IL-23/Th17 Axis

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiang-Min Liu ◽  
Quan-Xin Jin ◽  
Manabu Fujimoto ◽  
Fang-Fang Li ◽  
Lin-Bo Jin ◽  
...  
Keyword(s):  
T Cells ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Human Keratinocytes ◽  
Skin Lesions ◽  
Orphan Receptor ◽  
Hacat Cells ◽  
Ifn Γ

Background: Psoriasis is a T help 17 (Th17) cell-mediated chronic inflammatory skin disease. Recent studies have shown that dihydroartemisinin (DHA) can significantly reduce experimental autoimmune encephalomyelitis and rheumatoid arthritis by regulating Th17 cells.Objective: To verify whether DHA can improve the symptoms of psoriasis and to further explore the possible mechanism.Methods: The efficiency of DHA was preliminary detected on human keratinocytes (HaCaT) cells in psoriatic condition. Then, imiquimod-induced psoriasis-like model in BALB/c mice was established to evaluate the effects of DHA in vivo.Results: Under the stimulation of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), DHA inhibited the proliferation of HaCaT cells and significantly affected the mRNA expression levels of IFN-γ, interleukin (IL), IL-17A and IL-23. DHA treatment reduced the severity of psoriasis-like skin and resulted in less infiltration of immune cells in skin lesions. DHA restored the expression of IFN-γ, IL-17A, and IL-23 in skins, as well as a decrease of cytokines and chemokines in skin supernatant. DHA also altered the cellular composition in the spleen, which is the makeup of the T cells, dendritic cells (DCs), and macrophages. DHA recovered Th17-related profile with decreased frequency of IL-17+CD4+T cells from splenocyte of mice. Furthermore, DHA also inhibited the concentration of IL-17 from Th17 cells and the expression of Th17 cell-related transcription factors retinoid-related orphan receptor-gamma t (ROR-γt) in vitro. In addition, phosphorylation of signal transducer and activator of transcription-3 (STAT3) was significantly reduced in DHA treatment mice, suggesting that the IL-23/Th17 axis plays a pivotal role.Conclusion: DHA inhibits the progression of psoriasis by regulating IL-23/Th17 axis and is expected to be an effective drug for the treatment of psoriasis.

scholarly journals Interleukin-12 Is the Optimum Cytokine To Expand Human Th17 Cells In Vitro

2009 ◽  
Vol 16 (6) ◽  
pp. 798-805 ◽  
Author(s):  
Soad Nady ◽  
James Ignatz-Hoover ◽  
Mohamed T. Shata
Keyword(s):  
T Cells ◽  
Peripheral Blood ◽  
Th17 Cells ◽  
Interleukin 12 ◽  
Interleukin 17 ◽  
Functional Evaluation ◽  
Optimum Conditions ◽  
T Helper ◽  
Ifn Γ

ABSTRACT Recently, a new lineage of CD4+ T cells in humans and in mice has been reported. This T helper cell secretes interleukin-17 (IL-17) and has been defined as T helper 17 (Th17). Th17 cells express the IL-23 receptor (IL-23R) and play an important pathogenic role in different inflammatory conditions. In this study, our aim was to characterize the optimum conditions for isolation and propagation of human peripheral blood Th17 cells in vitro and the optimum conditions for isolation of Th17 clones. To isolate Th17 cells, two steps were taken. Initially, we negatively isolated CD4+ T cells from peripheral blood mononuclear cells of a normal human blood donor. Then, we isolated the IL-23R+ cells from the CD4+ T cells. Functional studies revealed that CD4+ IL-23R+ cells could be stimulated ex vivo with anti-CD3/CD28 to secrete both IL-17 and gamma interferon (IFN-γ). Furthermore, we expanded the CD4+ IL-23R+ cells for 1 week in the presence of anti-CD3/CD28, irradiated autologous feeder cells, and different cytokines. Our data indicate that cytokine treatment increased the number of propagated cells 14- to 99-fold. Functional evaluation of the expanded number of CD4+ IL-23R+ cells in the presence of different cytokines with anti-CD3/CD28 revealed that all cytokines used (IL-2, IL-7, IL-12, IL-15, and IL-23) increased the amount of IFN-γ secreted by IL-23R+ CD4+ cells at different levels. Our results indicate that IL-7 plus IL-12 was the optimum combination of cytokines for the expansion of IL-23R+ CD4+ cells and the secretion of IFN-γ, while IL-12 preferentially stimulated these cells to secrete predominately IL-17.

scholarly journals Essentials of Th17 cell commitment and plasticity

Blood ◽  
2013 ◽  
Vol 121 (13) ◽  
pp. 2402-2414 ◽  
Author(s):  
Pawel Muranski ◽  
Nicholas P. Restifo
Keyword(s):  
Th17 Cells ◽  
T Regulatory Cells ◽  
Adoptive Cell Transfer ◽  
Orphan Receptor ◽  
Immune Memory ◽  
Th22 Cells ◽  
Follicular Helper ◽  
New Findings ◽  
Cell Commitment

Abstract CD4+ T helper (Th) cells exist in a variety of epigenetic states that determine their function, phenotype, and capacity for persistence. These polarization states include Th1, Th2, Th17, and Foxp3+ T regulatory cells, as well as the more recently described T follicular helper, Th9, and Th22 cells. Th17 cells express the master transcriptional regulator retinoic acid–related orphan receptor γ thymus and produce canonical interleukin (IL)-17A and IL-17F cytokines. Th17 cells display a great degree of context-dependent plasticity, as they are capable of acquiring functional characteristics of Th1 cells. This late plasticity may contribute to the protection against microbes, plays a role in the development of autoimmunity, and is necessary for antitumor activity of Th17 cells in adoptive cell transfer therapy models. Moreover, plasticity of this subset is associated with higher in vivo survival and self-renewal capacity and less senescence than Th1 polarized cells, which have less plasticity and more phenotypic stability. New findings indicate that subset polarization of CD4+ T cells not only induces characteristic patterns of surface markers and cytokine production but also has a maturational aspect that affects a cell’s ability to survive, respond to secondary stimulation, and form long-term immune memory.

scholarly journals ABD-Derived Protein Blockers of Human IL-17 Receptor A as Non-IgG Alternatives for Modulation of IL-17-Dependent Pro-Inflammatory Axis

2018 ◽  
Vol 19 (10) ◽  
pp. 3089 ◽  
Author(s):  
Marie Hlavničková ◽  
Milan Kuchař ◽  
Radim Osička ◽  
Lucie Vaňková ◽  
Hana Petroková ◽  
...  
Keyword(s):  
Cell Surface ◽  
Clinical Manifestations ◽  
Cell Surface Receptor ◽  
Enzyme Linked Immunosorbent Assay ◽  
Interleukin 17 ◽  
Normal Human Skin ◽  
High Affinity ◽  
Th 17 ◽  
Surface Receptor

Interleukin 17 (IL-17) and its cognate receptor A (IL-17RA) play a crucial role in Th17 cells-mediated pro-inflammatory pathway and pathogenesis of several autoimmune disorders including psoriasis. IL-17 is mainly produced by activated Th-17 helper cells upon stimulation by IL-23 and, via binding to its receptors, mediates IL-17-driven cell signaling in keratinocytes. Hyper-proliferation of keratinocytes belongs to major clinical manifestations in psoriasis. To modulate IL-17-mediated inflammatory cascade, we generated a unique collection of IL-17RA-targeting protein binders that prevent from binding of human IL-17A cytokine to its cell-surface receptor. To this goal, we used a highly complex combinatorial library derived from scaffold of albumin-binding domain (ABD) of streptococcal protein G, and ribosome display selection, to yield a collection of ABD-derived high-affinity ligands of human IL-17RA, called ARS binders. From 67 analyzed ABD variants, 7 different sequence families were identified. Representatives of these groups competed with human IL-17A for binding to recombinant IL-17RA receptor as well as to IL-17RA-Immunoglobulin G chimera, as tested in enzyme-linked immunosorbent assay (ELISA). Five ARS variants bound to IL-17RA-expressing THP-1 cells and blocked binding of human IL-17 cytokine to the cell surface, as tested by flow cytometry. Three variants exhibited high-affinity binding with a nanomolar Kd value to human keratinocyte HaCaT cells, as measured using Ligand Tracer Green Line. Upon IL-17-stimulated activation, ARS variants inhibited secretion of Gro-α (CXCL1) by normal human skin fibroblasts in vitro. Thus, we identified a novel class of inhibitory ligands that might serve as immunosuppressive IL-17RA-targeted non-IgG protein antagonists.

scholarly journals Oleuropein modulates over-proliferation of keratinocytes in mice with imiquimodmediated psoriasis and inhibits differentiation of TH17 cells through the JAK3/STAT3 axis

2020 ◽  
Author(s):  
Quan Shi ◽  
Qi He ◽  
Weiming Chen ◽  
Jianwen Long ◽  
Bo Zhang
Keyword(s):  
T Cells ◽  
In Silico ◽  
Th17 Cells ◽  
Skin Lesions ◽  
Docking Studies ◽  
Inflammatory Disorder ◽  
T Helper 17 ◽  
In Silico Docking

IntroductionOleuropein (OLP) is polyphenol obtained from olive oil; it is proved in Chinese traditional medicine for its use in disorders including autoimmune and inflammatory disorders. Psoriasis (PSR) is an autoimmune and inflammatory disorder triggered by T-helper-17 (Th17) cells.Material and methodsWe developed an imiquimod (IMQ)-mediated PSR model in mice to study the anti-inflammatory role of OLP in psoriasis. The mice were given 50 mg/kg and 100 mg/kg dose of OLP. Histology was done to assess the inflammation of lesions. Western blot analysis was done for JAK3/STAT3 in isolated T cells, expression of RORgt was done by RT-PCR. The In silico molecular docking studies were done for interaction of OLP with target protein STAT3 and JAK3.ResultsTreatment of OLP attenuated proliferation in IMQ-mediated keratinocytes, improved infiltration of CD3+ cells in the skin lesions and in CD4+ and CD8+ T cells and also ameliorated the levels of cytokines. In in vitro studies in isolated T cells, OLP blocked the differentiation of Th17 cells and also the levels of IL-17 and the JAK3/STAT3 pathway. The in silico docking showed that OLP had potential binding affinity with JAK3 and STAT3 which was parallel to in vivo and in vitro findings.ConclusionsOLP ameliorates psoriasis skin lesions by blocking Th17-mediated inflammation. OLP may be an interesting molecule for treating autoimmunity in psoriasis.

Preclinical Safety and Pharmacology of an Anti-Human Interleukin-13 Monoclonal Antibody in Normal Macaques and in Macaques with Allergic Asthma

2008 ◽  
Vol 27 (5) ◽  
pp. 351-358 ◽  
Author(s):  
Pauline L. Martin ◽  
Dusti Fisher ◽  
William Glass ◽  
Karyn O’Neil ◽  
Anuk Das ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Allergic Asthma ◽  
Immunoglobulin E ◽  
Cynomolgus Macaque ◽  
Lavage Fluid ◽  
Antigen Challenge ◽  
Interleukin 13 ◽  
Lung Eosinophilia

Interleukin-13 (IL-13) plays a central role in chronic airway diseases, including asthma. These studies were conducted to evaluate the safety of administration of a human anti-IL-13 monoclonal antibody (mAb) to normal macaques and in macaques with allergic asthma. In addition, serum and bronchioalveolar lavage fluid were collected from allergic cynomolgus macaques in order to identify potential surrogate markers of IL-13 pharmacology that could be useful for subsequent clinical trials. In vitro studies demonstrated that the anti-IL-13 mAb inhibited the pharmacological actions of both human and cynomolgus macaque IL-13. Allergic macaques were treated systemically with 10 mg/kg anti-IL-13 mAb 1 day prior to inhaled Ascaris suum antigen challenge. Normal macaques were dosed intravenously with anti-IL-13 once per week for 3 weeks at doses of 10 or 50 mg/kg. Treatment of macaques with the anti-IL-13 mAb was not associated with any toxicologically significant findings. A slight treatment-related but nonadverse decrease in platelet counts was observed in both the normal and allergic macaques. In allergic macaques, the anti-IL-13 mAb treatment did not affect lung function, lung eosinophilia, or serum or BAL immunoglobulin E (IgE) concentrations but did produce a reduction in BAL and serum eotaxin concentrations ( p < .05) at 6 h post antigen challenge. This study shows that administration of an anti-IL-13 mAb was well tolerated in both normal and allergic asthmatic macaques and that serum eotaxin concentrations may be a useful early in vivo marker for evaluating IL-13 inhibition in patients with asthma.

scholarly journals A Novel Role for IL-6 Receptor Classic Signaling: Induction of RORγt+Foxp3+ Tregs with Enhanced Suppressive Capacity

2019 ◽  
Vol 30 (8) ◽  
pp. 1439-1453 ◽  
Author(s):  
Julia Hagenstein ◽  
Simon Melderis ◽  
Anna Nosko ◽  
Matthias T. Warkotsch ◽  
Johannes V. Richter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adoptive Transfer ◽  
Th17 Cells ◽  
Inflammatory Diseases ◽  
Double Positive ◽  
T Effector Cells ◽  
Suppressive Capacity

BackgroundNew therapies blocking the IL-6 receptor (IL-6R) have recently become available and are successfully being used to treat inflammatory diseases like arthritis. Whether IL-6 blockers may help patients with kidney inflammation currently remains unknown.MethodsTo learn more about the complex role of CD4+ T cell-intrinsic IL-6R signaling, we induced nephrotoxic nephritis, a mouse model for crescentic GN, in mice lacking T cell–specific IL-6Ra. We used adoptive transfer experiments and studies in reporter mice to analyze immune responses and Treg subpopulations.ResultsLack of IL-6Ra signaling in mouse CD4+ T cells impaired the generation of proinflammatory Th17 cells, but surprisingly did not ameliorate the course of GN. In contrast, renal damage was significantly reduced by restricting IL-6Ra deficiency to T effector cells and excluding Tregs. Detailed studies of Tregs revealed unaltered IL-10 production despite IL-6Ra deficiency. However, in vivo and in vitro, IL-6Ra classic signaling induced RORγt+Foxp3+ double-positive Tregs (biTregs), which carry the trafficking receptor CCR6 and have potent immunoregulatory properties. Indeed, lack of IL-6Ra significantly reduced Treg in vitro suppressive capacity. Finally, adoptive transfer of T cells containing IL-6Ra−/− Tregs resulted in severe aggravation of GN in mice.ConclusionsOur data refine the old paradigm, that IL-6 enhances Th17 responses and suppresses Tregs. We here provide evidence that T cell–intrinsic IL-6Ra classic signaling indeed induces the generation of Th17 cells but at the same time highly immunosuppressive RORγt+ biTregs. These results advocate caution and indicate that IL-6–directed therapies for GN need to be cell-type specific.

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